Intellectual disability (ID) is a common untreatable neurological disorder that affects a significant portion of the US population. ID is a major burden to the family as associated health care costs are high and patients with ID are frequently reliant upon family members for their activities of daily living. Little is known about the genetic and molecular mechanisms underlying ID and treatment options are limited to supportive care. One way to improve therapies for ID could be by identifying novel genetic pathways regulating neural development and function. The knowledge gained from these studies will be useful for future development of clinically relevant treatment options for ID patients as well as improve genetic counseling for families. Using whole exome sequencing; I have identified a 3 novel gene mutations in families with inherited progressive microcephaly and ID. These genes encode proteins involved in mRNA processing and nuclear export. Therefore, I hypothesize that mutations in these genes will affect the processing or cellular localization of a subset of mRNAs required for neural viability. To test this hypothesis, I have proposed the following aims: 1. Investigate how mutations in these genes affect neural progenitor cell viability and growth, and maturation of neurons in vitro and in vivo. 2. Determine whether the mutations in these genes alter mRNA splicing, abundance, and cellular localization. 3. Identify direct mRNA targets of these proteins by performing RNA immunoprecipitation and sequencing (RIP-seq). Understanding disease onset and progression as well as the underlying cellular and molecular changes associated with mutations in causal ID genes will provide insight into basic human developmental processes in addition to novel disease mechanisms in patients with ID.